Daily administration of o,p'-DDD (50 mg/kg, o.p.) to dogs for two weeks resulted in adrenal atrophy, necrosis, and subsequent loss in the content of adrenal cytochrome P-450. When a single dose of o,p'--DDD (50 mg/kg) was administered intravenously, moderate necrosis of the cells in the zona fasciculata occurred within 4 to 5 hr and was characterized enzymatically by a 30-50 percent loss in the activity of mitochondrial and microsomal cytochrome P-450 enzymes. The latter effects of o,p'-DDD treatment were prevented when the dogs were pretreated with an intravenous dose of spironolactone (100 mg/kg). The studies with spironolactone, which depletes the adrenal content of cytochrome P-450 dependent enzymes, suggest that oxidation or hydroxylation of o,p'-DDD by a cytochrome P-450 dependent enzyme may be prerequisite for adrenal necrosis to occur.